Sequences related to SUMO interaction motifs in herpes simplex virus 1 protein ICP0 act cooperatively to stimulate virus infection

Everett, R.D., Boutell, C. , Pheasant, K., Cuchet-Lourenco, D. and Orr, A. (2014) Sequences related to SUMO interaction motifs in herpes simplex virus 1 protein ICP0 act cooperatively to stimulate virus infection. Journal of Virology, 88(5), pp. 2763-2774. (doi: 10.1128/JVI.03417-13) (PMID:24352468) (PMCID:PMC3958091)

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Abstract

Herpes simplex virus type 1 immediate-early protein ICP0 is an E3 ubiquitin ligase of the RING finger class that degrades several cellular proteins during infection. This activity is essential for its functions in stimulating efficient lytic infection and productive reactivation from latency. ICP0 targets a number of proteins that are modified by the small ubiquitin-like SUMO family of proteins, and it includes a number of short sequences that are related to SUMO interaction motifs (SIMs). Therefore, ICP0 has characteristics that are related to those of cellular SUMO-targeted ubiquitin ligase enzymes. Here, we analyze the impact of mutation of a number of SIM-like sequences (SLSs) within ICP0 on HSV-1 replication and gene expression and their requirement for ICP0-mediated degradation of both sumoylated and unmodified promyelocytic leukemia (PML) and other sumoylated cellular proteins. One SLS in the central portion of the ICP0 sequence (SLS4) was found to be absolutely required for targeting cellular sumoylated species in general and sumoylated forms of PML other than those of PML isoform I. Mutation of a group of SLSs in the C-terminal quarter of ICP0 also reduced ICP0-mediated degradation of sumoylated PML in a cooperative manner. Although mutation of individual SLSs caused only modest decreases in viral replication, combined mutation of SLS4 with SLS sequences in the C-terminal quarter of the protein reduced plaque formation efficiency by up to two orders of magnitude. These results provide further evidence that the biological activities of ICP0 are connected with host cell sumoylation events.<p></p> IMPORTANCE Herpes simplex virus type 1 protein ICP0 plays important roles in regulating the initial stages of lytic infection and productive reactivation from latency. ICP0 mediates its effects through inducing the degradation of cellular proteins that have repressive effects on viral gene expression. An increasing number of cellular proteins are known to be sensitive to ICP0-mediated degradation; therefore, it is important to understand how ICP0 selects its substrates for degradation. This study identifies sequence motifs within ICP0 that are involved in targeting cellular proteins that are modified by the SUMO family of ubiquitin-like proteins and describes how mutation of combinations of these motifs causes a 100-fold defect in viral infectivity.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Everett, Professor Roger and Orr, Mrs Anne and Pheasant, Miss Kathleen and Boutell, Dr Chris and Cuchet, Dr Delphine
Authors: Everett, R.D., Boutell, C., Pheasant, K., Cuchet-Lourenco, D., and Orr, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:Elsevier
ISSN:0022-538X
ISSN (Online):1098-5514
Copyright Holders:Copyright © 2010 Elsevier Inc.
First Published:First published in Journal of Virology 88(5):2763-2774
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656521The role of ubiquitin and ubiquitin-like proteins during viral infectionChris BoutellMedical Research Council (MRC)MC_UU_12014/5MVLS III - CENTRE FOR VIRUS RESEARCH
656501Regulation of the initial stages of herpes simplex virus lytic infection and reactivation from latencyRoger EverettMedical Research Council (MRC)MC_UU_12014/4MVLS III - CENTRE FOR VIRUS RESEARCH